Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and has emerged as one of the pre-eminent public health concerns of the 21st century, especially in the case of hospital-acquired infections. According to data from the Centers for Disease Control and Prevention (CDC) available in 2008, the six so-called ESKAPE bacteria (Enterococcus faecium (gram positive), Staphylococcus aureus (gram positive), Klebsiella pneumoniae (gram negative), Acinetobacter baumanii (gram negative), Pseudomonas aeruginosa (gram negative), and Enterobacter (gram negative)) are responsible for two thirds of all health care-associated infections. The increasing prevalence of antibiotic-resistant bacterial infections seen in clinical practice stems from antibiotic use both within human medicine and veterinary medicine in which the use of antibiotics can increase selective pressure in a population of bacteria to allow the resistant bacteria to thrive and the susceptible bacteria to die off.
Infection by several drug-resistant Gram-negative bacteria—such as multidrug-resistant (MDR) Pseudomonas aeruginosa and carbapenem-resistant Klebsiella species is of great concern. The therapeutic options for these pathogens are so limited that clinicians are often forced to use older, previously discarded drugs, which are associated with significant toxicity.
With respect to gram-positive bacteria, the percentage of bloodstream infections caused by antibiotic-resistant gram-positive bacteria is increasing. As of 2006, approximately 60% of staphylococcal infections in intensive care units in the United States were caused by methicillin-resistant Staphylococcus aureus (MRSA), with percentages continuing to rise. Hospital-acquired MRSA strains are generally multidrug-resistant. As a means of highlighting the scale of the problem at hand, more people now die of MRSA infection in US hospitals than of HIV/AIDS and tuberculosis combined. Vancomycin is the standard treatment for serious MRSA infections, but cases of vancomycin-resistant Staphylococcus aureus (VRSA) also emerge. The increase in resistant Gram-positive strains may be explained, in part, by scientists concentrating in the 1970s and 1980s on the development of drugs active against Gram-negative pathogens, thereby permitting the slow evolution and selection of resistant Gram-positive bacteria.
Furthermore, multi-drug resistant (MDR) infections are also increasing and infections now occur that are resistant to all current antibacterial options (so-called pan-antibiotic-resistance). As resistance towards antibiotics becomes more common, a greater need for alternative treatments arises. However, despite a push for new antibiotic therapies, there has been a continued decline in the number of newly approved drugs. Antibiotic resistance and, in particular, the antibiotic resistance of gram-positive bacteria therefore poses a significant global health problem.
U.S. Pat. No. 4,012,414 discloses 2-furylimidazoles in which, with the exception of the bond to the furan ring, the imidazoles are unsubstituted. These compounds are disclosed to be suitable for use as antidepressants.
EP 0251380 discloses 2-furanylimidizoles for use as cardiotonic agents whereby the two carbon atoms of the imidazole ring which are not bonded to the furan ring may be substituted with H, methyl or ethyl.
It is therefore an object of the present invention to provide chemical species which can overcome the above-highlighted deficiencies in the treatment of mammalian microbial infections, in particular those resulting from gram-positive bacteria, and especially gram-positive bacteria strains known to show resistance to existing antibiotics/therapies.